Epstein-Barr病毒动态检测在鼻咽癌诊断和治疗中的意义
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摘要
背景与目的:
EB病毒(Epstein-Barr virus,EBV)与鼻咽癌的发生发展密切相关,血清EBV-VCA/IgA检测已广泛用于鼻咽癌的筛查。新近研究发现鼻咽癌患者血浆EBV-DNA定量检测在鼻咽癌早期诊断中有一定的价值,但EBV-VCA/IgA和EBV-DNA在鼻咽癌治疗过程中动态变化研究尚缺。本文通过分析鼻咽癌患者治疗过程中EBV-VCA/IgA及EBV-DNA动态变化规律,探索二者在鼻咽癌治疗转归中的意义。
方法:
1.EB病毒阳性鼻咽癌患者确定中南大学湘雅医院2006年5月至2008年1月耳鼻喉科门诊疑似鼻咽癌患者,病理活检确定为鼻咽癌,采用免疫组化检测活检组织LMP1蛋白表达,获得EB病毒阳性的鼻咽癌患者。
2.观察对象确定和标本采集EB病毒阳性的鼻咽癌患者,同意配合进行相关检查,纳入观察对象,常规进行放射治疗。分别在治疗前和治疗后1、2、3、4、5、6、7周及3月后复查时采集患者静脉血收集血清、血浆。
3.血浆标本采用巢式荧光定量PCR的方法,在Mx3000p型检测仪上定量检测EBV-DNA的含量,分别计算患者在不同时间点的EBV-DNA拷贝数中位数,将其绘制成波动图。
4.血清标本采用ELISA技术检测EBV-VCA/IgA的水平,根据OD值将其绘制成波动图。
5.利用核磁共振物理成像技术,测定鼻咽癌患者肿瘤大小。
结果:
1.用免疫组织化学的方法分析疑似鼻咽癌患者鼻咽组织中LMP1蛋白的表达,LMP1蛋白在鼻咽组织中位于细胞浆或细胞膜。80例组织中,34例表达阳性,阳性率为42.5%。
2.用定量PCR动态监测鼻咽癌治疗过程中血浆EBV-DNA拷贝数,鼻咽癌患者血浆EBV-DNA的检出率为96.4%(27/28),中位数为1800 cones/μl(0～22100 copies/μl);治疗后EBV-DNA成动态变化,多数病例(18/30)治疗后EBV-DNA拷贝数降低,部分患者(9/30)治疗后EBV-DNA拷贝数升高。
3.24例患者治疗前血清EBV-VCA/IgA表达阳性,阳性率为85.7%。在30例鼻咽癌患者治疗前和治疗后1、2、3、4、5、6、7周及3月后复查9次EBV-VCA/IgA检测中,多数病例(17/24)治疗后EBV-VCA/IgA降低,部分患者(6/24)治疗后EBV-VCA/IgA变化不明显。
4.通过分析EBV-VCA/IgA、EBV-DNA与鼻咽癌肿瘤大小相关性,发现EBV-DNA拷贝数与鼻咽癌肿瘤体积有一定相关性。
结论:
1.将巢式PCR技术与荧光定量PCR技术结合,成功建立了血浆EBV-DNA的检测方法——巢式荧光定量PCR。
2.通过动态监测鼻咽癌患者治疗过程中血浆EBV-DNA拷贝数,明确了EBV-DNA水平与鼻咽癌治疗疗效、肿瘤大小的关系。EBV-DNA在一定程度上反映鼻咽癌肿瘤大小。
3.EBV-VCA/IgA和EBV-DNA拷贝数联合用于鼻咽癌的早期筛查,具有一定的临床价值。
Background and objective:
Epstein-Barr virus(EBV)is closely associated with nasopharyngeal carcinoma(NPC),and EBV-VCA/IgA is served as a biomarker of NPC in early stage.Recently,it was reported that EBV-DNA quantitive assay in plasma had some clinical significance to NPC early diagnosis.It has not been illuminated whether EBV-DNA was associated with NPC tumor size. In this present,the dynamic study of EBV-VCA/IgA and EBV-DNA was conducted in treatment progress,and the association of EBV-DNA and NPC tumor size was investigated.
Methods:
1.To definite the NPC patients with EBV.The suspected NPC outpatients in ENT of Xiangya Hospital were pathologically diagnosed and EBV-LMP1 was detected in biopsy tissues by immunohistochemistry from May 2006 to January 2008.
2.To determine patients and collect samples.NPC patients were as the objects if the NPC patients with positive EBV agreed to join in experiment group.The plasma and serum were collected at pre-treatment and one,two,three,four,five,six,seven weeks and three months after treatment.
3.The plasma EBV-DNA concentration was analyzed by using fluorescent quantitative nested-PCR technique in Mx3000p.The median concentration was calculated and dynamic pictures were drawn.
4.The levels of EBV-VCA/IgA were detected through ELISA assay and dynamic pictures were drawn by OD.
5.The NPC tumor size was measured using magnetic resonance imaging technology.
Results:
1.The results of immunohistochemistry showed that LMP1 protein expressed in cytoplasm or cytomembraneo The positive rate was 42.5% (34/80).
2.EBV-DNA was detected in 27/28 NPC patients plasma,and positive rate was 96.4%.The median concentration was 1800 copies/μ1 (range:0-22100).Among 30 cases,EBV-DNA were declining in 18 cases and increasing in 9 cases.
3.24/28 cases were detectable for serum EBV-VCA/IgA.During treatment EBV-VCA/IgA were declining in 17 cases and increasing in 6 cases.
4.By analyzing relationships between EBV-VCA/IgA or EBV-DNA and tumor size,we found EBV-DNA were associated with tumor volume to a certain extent.
Conclusions:
1.The fluorescent quantitative nested-PCR was established for detecting EBV-DNA by combining the nested PCR with the fluorescent quantitative PCR.
2.It was clear that the EBV-DNA was closed related with curative effect and tumor burden through dynamic study.
3.The EBV-VCA/IgA and EBV-DNA could be used to screen NPC patients and had clinical significance.
EB病毒(Epstein-Barr virus,EBV)与鼻咽癌的发生发展密切相关,血清EBV-VCA/IgA检测已广泛用于鼻咽癌的筛查。新近研究发现鼻咽癌患者血浆EBV-DNA定量检测在鼻咽癌早期诊断中有一定的价值,但EBV-VCA/IgA和EBV-DNA在鼻咽癌治疗过程中动态变化研究尚缺。本文通过分析鼻咽癌患者治疗过程中EBV-VCA/IgA及EBV-DNA动态变化规律,探索二者在鼻咽癌治疗转归中的意义。
方法:
1.EB病毒阳性鼻咽癌患者确定中南大学湘雅医院2006年5月至2008年1月耳鼻喉科门诊疑似鼻咽癌患者,病理活检确定为鼻咽癌,采用免疫组化检测活检组织LMP1蛋白表达,获得EB病毒阳性的鼻咽癌患者。
2.观察对象确定和标本采集EB病毒阳性的鼻咽癌患者,同意配合进行相关检查,纳入观察对象,常规进行放射治疗。分别在治疗前和治疗后1、2、3、4、5、6、7周及3月后复查时采集患者静脉血收集血清、血浆。
3.血浆标本采用巢式荧光定量PCR的方法,在Mx3000p型检测仪上定量检测EBV-DNA的含量,分别计算患者在不同时间点的EBV-DNA拷贝数中位数,将其绘制成波动图。
4.血清标本采用ELISA技术检测EBV-VCA/IgA的水平,根据OD值将其绘制成波动图。
5.利用核磁共振物理成像技术,测定鼻咽癌患者肿瘤大小。
结果:
1.用免疫组织化学的方法分析疑似鼻咽癌患者鼻咽组织中LMP1蛋白的表达,LMP1蛋白在鼻咽组织中位于细胞浆或细胞膜。80例组织中,34例表达阳性,阳性率为42.5%。
2.用定量PCR动态监测鼻咽癌治疗过程中血浆EBV-DNA拷贝数,鼻咽癌患者血浆EBV-DNA的检出率为96.4%(27/28),中位数为1800 cones/μl(0～22100 copies/μl);治疗后EBV-DNA成动态变化,多数病例(18/30)治疗后EBV-DNA拷贝数降低,部分患者(9/30)治疗后EBV-DNA拷贝数升高。
3.24例患者治疗前血清EBV-VCA/IgA表达阳性,阳性率为85.7%。在30例鼻咽癌患者治疗前和治疗后1、2、3、4、5、6、7周及3月后复查9次EBV-VCA/IgA检测中,多数病例(17/24)治疗后EBV-VCA/IgA降低,部分患者(6/24)治疗后EBV-VCA/IgA变化不明显。
4.通过分析EBV-VCA/IgA、EBV-DNA与鼻咽癌肿瘤大小相关性,发现EBV-DNA拷贝数与鼻咽癌肿瘤体积有一定相关性。
结论:
1.将巢式PCR技术与荧光定量PCR技术结合,成功建立了血浆EBV-DNA的检测方法——巢式荧光定量PCR。
2.通过动态监测鼻咽癌患者治疗过程中血浆EBV-DNA拷贝数,明确了EBV-DNA水平与鼻咽癌治疗疗效、肿瘤大小的关系。EBV-DNA在一定程度上反映鼻咽癌肿瘤大小。
3.EBV-VCA/IgA和EBV-DNA拷贝数联合用于鼻咽癌的早期筛查,具有一定的临床价值。
Background and objective:
Epstein-Barr virus(EBV)is closely associated with nasopharyngeal carcinoma(NPC),and EBV-VCA/IgA is served as a biomarker of NPC in early stage.Recently,it was reported that EBV-DNA quantitive assay in plasma had some clinical significance to NPC early diagnosis.It has not been illuminated whether EBV-DNA was associated with NPC tumor size. In this present,the dynamic study of EBV-VCA/IgA and EBV-DNA was conducted in treatment progress,and the association of EBV-DNA and NPC tumor size was investigated.
Methods:
1.To definite the NPC patients with EBV.The suspected NPC outpatients in ENT of Xiangya Hospital were pathologically diagnosed and EBV-LMP1 was detected in biopsy tissues by immunohistochemistry from May 2006 to January 2008.
2.To determine patients and collect samples.NPC patients were as the objects if the NPC patients with positive EBV agreed to join in experiment group.The plasma and serum were collected at pre-treatment and one,two,three,four,five,six,seven weeks and three months after treatment.
3.The plasma EBV-DNA concentration was analyzed by using fluorescent quantitative nested-PCR technique in Mx3000p.The median concentration was calculated and dynamic pictures were drawn.
4.The levels of EBV-VCA/IgA were detected through ELISA assay and dynamic pictures were drawn by OD.
5.The NPC tumor size was measured using magnetic resonance imaging technology.
Results:
1.The results of immunohistochemistry showed that LMP1 protein expressed in cytoplasm or cytomembraneo The positive rate was 42.5% (34/80).
2.EBV-DNA was detected in 27/28 NPC patients plasma,and positive rate was 96.4%.The median concentration was 1800 copies/μ1 (range:0-22100).Among 30 cases,EBV-DNA were declining in 18 cases and increasing in 9 cases.
3.24/28 cases were detectable for serum EBV-VCA/IgA.During treatment EBV-VCA/IgA were declining in 17 cases and increasing in 6 cases.
4.By analyzing relationships between EBV-VCA/IgA or EBV-DNA and tumor size,we found EBV-DNA were associated with tumor volume to a certain extent.
Conclusions:
1.The fluorescent quantitative nested-PCR was established for detecting EBV-DNA by combining the nested PCR with the fluorescent quantitative PCR.
2.It was clear that the EBV-DNA was closed related with curative effect and tumor burden through dynamic study.
3.The EBV-VCA/IgA and EBV-DNA could be used to screen NPC patients and had clinical significance.
引文
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[1]Zhou H,Calaf GM,Hei TK.Malignant transformation of human bronchial epithelial cells with the tobacco-specific nitrosamine,4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone.Int J Cancer,2003,106(6):821-826
[2]Wang H,Tan W,Hao B,et al.Substantial reduction in risk of lung adenocarcinoma associated with genetic polymorphism in CYP2A13,the most active cytochrome P450 for the metabolic activation of tobacco-specific carcinogen NNK.Cancer Res,2003,63(22):8057-8061
[3]Liu L,Qin X,Gerson SL.Reduced lung tumorigenesis in human methylguanine DNA-methyltransferase transgenic mice achieved by expression of transgene within the target cell.Carcinogenesis,1999,20(2):279-84.
[4]孙红琰,龚诒芬,王全立,等.烟草特异亚硝胺NNK诱发人胎肺细胞癌变启动模型的建.中国公共卫生学报,1998,17(5):282-283
[5]杨陟华,朱茂祥,龚诒芬,等.NNK诱发人支气管上皮细胞恶性转化及氧化损伤机理研究.癌变·畸变·突变,1999,11(4):184-187
[6]Rioux N,Castonguay A.4-(methylrtitrosamino)-1-(3-pyridyl)-1-butanone modulation of cytokine release in U937 human macrophages.Cancer Immunol Immunoter,2001,49(12):663-670
[7]张同梅,赖百塘.烟草特有亚硝胺NNK与肺癌的关系.中华流行病学杂志,2000,26(2):140-142
[8]张玉霞,赖百塘,陈洪雷,等.烟草致癌原NNK诱发大鼠肺癌前病变的实验研究.中国肺癌杂志,2006,9(2):152-156
[9]Schuller HM,Plummer HK 3rd,Jull BA.Receptor-mediated effects of nicotine and its nitrosated derivative NNK on pulmonary neuroendocrine cells.Anat Rec A Discov Mol Cell Evol Biol,2003,270(1):51-58
[10]Jull BA,Plummer HK 3rd,Schuller HM.Nicotinic receptor-mediated activation by the tobacco-specific nitrosamine NNK of a Raf-1/MAP kinase pathway,resulting in phosphorylation of c-myc in human small cell lung carcinoma cells and pulmonary neuroendocrine cells.J Cancer Res Clin Oncol,2001,127(12):707-717
[11]Wu WK,Wong HP,Luo SW,et al.4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone from cigarette smoke stimulates colon cancer growth via beta-adrenoceptors.Cancer Res,2005,65(12):5272-5277
[12]Schuller HM.Mechanisms of smoking-related lung and pancreatic adenocarcinoma development.Nature Reviews Cancer,2002,2(6):455-463
[13]Schuller HM,Cekanova M.NNK-induced hamstar lung adenocarcinomas over-express bera2-adrenergic and EGFR signaling pathways.Lung Cancer,2005,49(1):35-45
[14]Lijinsky W,Kovatch RM.Carcinogenic effects in rats of nitrosopiperazines administered intravesically:possible implications for the use of piperazine.Cancer Lett,1993,74(1-2):101-103
[15]唐发清,蒋海鹰,段朝军,等.二亚硝基哌嗪诱发SD大鼠鼻咽癌变中端粒酶和端粒酶RNA的表达。中国病理生理杂志,2000,16(10):1053
[16]唐发清,蒋海鹰,段朝军,等。鼻咽上皮癌变过程中端粒酶活性和端粒酶RNA的表达。中华病理学杂志,2001,30(2):125-128
[17]Tan W,Song N,Wang GQ,et al.Impact of genetic polymorphisms in cytochrome P450 2E1 and glutathione S-transferases M1,T1,and P1 on susceptibility to esophageal cancer among high-risk individuals in China.Cancer Epidemiol,Biomarkers Prey,2000,9:551-556
[18]俞维萍,陈坤,马新源,等。细胞色素P450 2E1基因Pst Ⅰ多态、腌制品与大肠癌关系的病例对照研究.中华预防医学杂志,2004,38(3):162-166
[19]贺智敏,王水良,陈主初.细胞色素P450 2E1在人鼻咽部的表达及体外表达模型的建立.癌变·畸变·突变,2001,13(4):262-263
[20]贺智敏,王水良,袁建辉,等.人细胞色素P450 2E1基因在胚胎鼻咽组织、鼻咽癌细胞和组织中的表达.癌症,2002,21(6):597-600
[21]Zhu JH,He ZM,Wang SL,et al.Effect of N,N'-dinitrosopiperazine on in vitro expression of human cytochrome P450 2E1.Chin Med J,2002,115(8):1229-1232
[22]Chen ZC,Pan SC,Yao KT.Chemical transformation of human embryonic nasopharyngeal epithelial cells in vitro.IARC Sci Publ,1991,(105):434-438
[23]Yunis JJ,Soreng AL,Bowe AE.Fragile sites are targets of diverse mutagens and carcinogens.Oncogene,1987,1(1):59-69
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[1]Zhou H,Calaf GM,Hei TK.Malignant transformation of human bronchial epithelial cells with the tobacco-specific nitrosamine,4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone.Int J Cancer,2003,106(6):821-826
[2]Wang H,Tan W,Hao B,et al.Substantial reduction in risk of lung adenocarcinoma associated with genetic polymorphism in CYP2A13,the most active cytochrome P450 for the metabolic activation of tobacco-specific carcinogen NNK.Cancer Res,2003,63(22):8057-8061
[3]Liu L,Qin X,Gerson SL.Reduced lung tumorigenesis in human methylguanine DNA-methyltransferase transgenic mice achieved by expression of transgene within the target cell.Carcinogenesis,1999,20(2):279-84.
[4]孙红琰,龚诒芬,王全立,等.烟草特异亚硝胺NNK诱发人胎肺细胞癌变启动模型的建.中国公共卫生学报,1998,17(5):282-283
[5]杨陟华,朱茂祥,龚诒芬,等.NNK诱发人支气管上皮细胞恶性转化及氧化损伤机理研究.癌变·畸变·突变,1999,11(4):184-187
[6]Rioux N,Castonguay A.4-(methylrtitrosamino)-1-(3-pyridyl)-1-butanone modulation of cytokine release in U937 human macrophages.Cancer Immunol Immunoter,2001,49(12):663-670
[7]张同梅,赖百塘.烟草特有亚硝胺NNK与肺癌的关系.中华流行病学杂志,2000,26(2):140-142
[8]张玉霞,赖百塘,陈洪雷,等.烟草致癌原NNK诱发大鼠肺癌前病变的实验研究.中国肺癌杂志,2006,9(2):152-156
[9]Schuller HM,Plummer HK 3rd,Jull BA.Receptor-mediated effects of nicotine and its nitrosated derivative NNK on pulmonary neuroendocrine cells.Anat Rec A Discov Mol Cell Evol Biol,2003,270(1):51-58
[10]Jull BA,Plummer HK 3rd,Schuller HM.Nicotinic receptor-mediated activation by the tobacco-specific nitrosamine NNK of a Raf-1/MAP kinase pathway,resulting in phosphorylation of c-myc in human small cell lung carcinoma cells and pulmonary neuroendocrine cells.J Cancer Res Clin Oncol,2001,127(12):707-717
[11]Wu WK,Wong HP,Luo SW,et al.4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone from cigarette smoke stimulates colon cancer growth via beta-adrenoceptors.Cancer Res,2005,65(12):5272-5277
[12]Schuller HM.Mechanisms of smoking-related lung and pancreatic adenocarcinoma development.Nature Reviews Cancer,2002,2(6):455-463
[13]Schuller HM,Cekanova M.NNK-induced hamstar lung adenocarcinomas over-express bera2-adrenergic and EGFR signaling pathways.Lung Cancer,2005,49(1):35-45
[14]Lijinsky W,Kovatch RM.Carcinogenic effects in rats of nitrosopiperazines administered intravesically:possible implications for the use of piperazine.Cancer Lett,1993,74(1-2):101-103
[15]唐发清,蒋海鹰,段朝军,等.二亚硝基哌嗪诱发SD大鼠鼻咽癌变中端粒酶和端粒酶RNA的表达。中国病理生理杂志,2000,16(10):1053
[16]唐发清,蒋海鹰,段朝军,等。鼻咽上皮癌变过程中端粒酶活性和端粒酶RNA的表达。中华病理学杂志,2001,30(2):125-128
[17]Tan W,Song N,Wang GQ,et al.Impact of genetic polymorphisms in cytochrome P450 2E1 and glutathione S-transferases M1,T1,and P1 on susceptibility to esophageal cancer among high-risk individuals in China.Cancer Epidemiol,Biomarkers Prey,2000,9:551-556
[18]俞维萍,陈坤,马新源,等。细胞色素P450 2E1基因Pst Ⅰ多态、腌制品与大肠癌关系的病例对照研究.中华预防医学杂志,2004,38(3):162-166
[19]贺智敏,王水良,陈主初.细胞色素P450 2E1在人鼻咽部的表达及体外表达模型的建立.癌变·畸变·突变,2001,13(4):262-263
[20]贺智敏,王水良,袁建辉,等.人细胞色素P450 2E1基因在胚胎鼻咽组织、鼻咽癌细胞和组织中的表达.癌症,2002,21(6):597-600
[21]Zhu JH,He ZM,Wang SL,et al.Effect of N,N'-dinitrosopiperazine on in vitro expression of human cytochrome P450 2E1.Chin Med J,2002,115(8):1229-1232
[22]Chen ZC,Pan SC,Yao KT.Chemical transformation of human embryonic nasopharyngeal epithelial cells in vitro.IARC Sci Publ,1991,(105):434-438
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